ME01528B - Processes and intermediates for the preparation of 1'-cyano-carbanucleoside analogs - Google Patents

Processes and intermediates for the preparation of 1'-cyano-carbanucleoside analogs

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Publication number
ME01528B
ME01528B MEP-2013-111A MEP11113A ME01528B ME 01528 B ME01528 B ME 01528B ME P11113 A MEP11113 A ME P11113A ME 01528 B ME01528 B ME 01528B
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alkyl
substituted
compound
formula
independently
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Thomas Butler
Aesop Cho
Benjamin R Graetz
Choung U Kim
Samuel E Metobo
Oliver L Saunders
Andrew W Waltman
Jie Xu
Lijun Zhang
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Gilead Sciences Inc
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Publication of ME01528B publication Critical patent/ME01528B/en

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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom

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Claims (20)

1. Postupak za proizvodnju jedinjenja Formule I: ili njene prihvatljive soli; gde: R1 je H, (C1-C8)alkil, (C4-C8)karbociklilalkil, (C1-C8)supstituisan alkil, (C2-C8)alkenil, (C2-C8)supstituisan alkenil, (C2-C8)alkinil, (C2-C8)supstituisan alkinil, ili aril(C1-C8)alkil; svaki R2a ili R2bje nezavisno H, F ili OR4; svaki R3 je nezavisno (C1-C8)alkil, (C1-C8)supstituisan alkil, C6-C20 aril, C6-C20 supstituisan aril, C2-C20 heterociklil, C2-C20 supstituisan heterociklil, C7-C20 arilalkil, C7-C20 supstituisan arilalkil, (C1-C8) alkoksi, ili (C1-C8) supstituisan alkoksi; svaki R4 ili R7 je nezavisno H, opciono supstituisan alil, -C(R5)2R6, Si(R3)3, C(O)R5, C(O)OR5, -(C(R5)2)m-R15 ili ili bilo koja dva R4 ili R' zajedno su -C(R19)2-, -C(O)- ili - Si(R3)2(X2)mSi(R3)2-; svaki R15 je nezavisno -O-C(R5)2R6, -Si(R3)3, C(O)0R5, -OC(O)R5 ili svaki R5, R18 ili R19 je nezavisno H, (C1-C8) alkil, (C1-C8) supstituisan alkil, (C2-C8)alkenil, (C2-C8) supstituisan alkenil, (C2-C8) alkinil, (C2-C8) supstituisan alkinil, C6- C20 aril, C6-C2o supstituisan aril, C2-C20 heterociklil, C2-C20 supstituisan heterociklil, C7-C20 arilalkil ili C7-C20 supstituisan arilalkil; svaki R6 je nezavisno C6-C2o aril, C6-C20 supstituisan aril, ili opciono supstituisan heteroaril; svaki Ra je nezavisno H, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, aril(C1-C8)alkil, (C4-C8)karbociklilalkil, -C(=O)R11,     -C(=O)0R11,     -C(=O)NR11R12,     -C(=O)SR11, -S(O)R11, -S(O)2R11, -S(O)(0R11), -S(O)2(0R11) ili -SO2NR11R12; X1 je C-R10 ili N; svaki X2 je O ili CH2; svaki m je 1 ili 2; svaki n je nezavisno 0, 1 ili 2; svaki R8 je halogen, NR11R12, N(R11)OR11, NR11NR11R12, N3, NO, N02, CHO, CH(=NR11), -CH=NHNR11, -CH=N(OR11), -CH(OR11)2, -C(=O)NR11R12, -C(=S) NR11R12, -C(-O)0R11, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C4-C8)karbociklilalkil, opciono supstituisan aril, opciono supstituisan heteroaril, -C(=O)(C1-C8)alkil, -S(O)n(C1-C8)alkil, aril(C1-C8)alkil, CN, OR11 ili SR11; svaki R9 ili R10je nezavisno H, halogen, NR11R12, N(R11)OR11, N(R11)N(R11)(R12), N3, NO, N02, CHO, CN, -CH(=NR11), -CH=NNH(R11), -CH=N(OR11), -CH(OR11)2, -C(=O)NR11R12, -C(=S)NR11R12, -C(=O)0R11, R11, OR11 ili SR11; svaki R11 ili R12 je nezavisno H, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8)karbociklil, (C4-C8)karbociklilalkil, opciono supstituisan aril, opciono supstituisan heteroaril, -C(=O)(CrC8)alkil, -S(O)n(C1-C8)alkil, aril(C1-C8)alkil ili Si(R3)3; ili R11 i R12 zajedno sa azotom za koji su oba vezana obrazuju 3 do 7-člani heterociklični prsten u kom bilo koji atom ugljenika navedenog heterocikličnog prstena može opciono biti zamenjen sa -O-, -S(O)n- ili -NRa-; ili R11 i R12 zajedno su -Si(R3)2(X2)mSi(R3)2-; svaki R20je nezavisno H, (C1-C8)alkil, supstituisan (C1-C8)alkil ili halo; pri čemu svaki (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil ili aril(C1-C8)alkil u svakom R1, R3, R4, R5, R6 R18 R19, R20, R11 ili R12 je, nezavisno, opciono supstituisan sa jednim ili više halo, hidroksi, CN, N3, N(Ra)2 ili ORa; i gde je jedan ili više atoma ugljenika, koji nisu krajnji u svakom od navedenih (C1-C8) alkila, opciono zamenjen sa -O-, -S(O)n- ili-NRa-; pomenuti postupak obuhvata: (a) obezbeđivanje jedinjenja Formule II ili njegove prihvatljive soli; u kome je R16: OH, OR18, -OC(O)OR18 ili -OC(O)R18; (b) obradu jedinjenja Formule II sa cijanidnim reagensom i Levvisovom kiselinom; na koji način se formira jedinjenje Formule I; uz uslov da kada je jedinjenje Formule II: gde X1 je CH ili N, R1 je CH3, R8 je NH2 i R9 je NH2 ili H ili; gde X1 je CH, R1 je CH3, R8 je OH i R9 je NH2 ili; gde X1 je CH, svaki R1 i R9 su H i R8 je NH2; onda cijanidni reagens nije (CH3)3SiCN ili pomenuta Lewisova kiselina nije BF3- O(CH2)CH3)2.1. Process for the production of a compound of Formula I: or an acceptable salt thereof; where: R1 is H, (C1-C8)alkyl, (C4-C8)carbocyclylalkyl, (C1-C8)substituted alkyl, (C2-C8)alkenyl, (C2-C8)substituted alkenyl, (C2-C8)alkynyl, (C2-C8)substituted alkynyl, or aryl(C1-C8)alkyl; each R 2a or R 2 is independently H, F or OR 4 ; each R3 is independently (C1-C8)alkyl, (C1-C8)substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heterocyclyl, C2-C20 substituted heterocyclyl, C7-C20 arylalkyl, C7-C20 substituted arylalkyl, (C 1 -C 8 ) alkoxy, or (C 1 -C 8 ) substituted alkoxy; each R4 or R7 is independently H, optionally substituted allyl, -C(R5)2R6, Si(R3)3, C(O)R5, C(O)OR5, -(C(R5)2)m-R15 or or any two R4 or R' together are -C(R19)2-, -C(O)- or -Si(R3)2(X2)mSi(R3)2-; each R15 is independently -O-C(R5)2R6, -Si(R3)3, C(O)0R5, -OC(O)R5 or each R5, R18 or R19 is independently H, (C1-C8) alkyl, (C1 -C8) substituted alkyl, (C2-C8)alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heterocyclyl, C2-C20 substituted heterocyclyl, C7-C20 arylalkyl or C7-C20 substituted arylalkyl; each R 6 is independently C 6 -C 20 aryl, C 6 -C 20 substituted aryl, or optionally substituted heteroaryl; each Ra is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, (C4-C8)carbocyclylalkyl, -C(=O)R11, -C(=O)0R11,     -C(=O)NR11R12,     -C(=O)SR11, -S(O)R11, -S(O)2R11, -S(O)(0R11), -S( O)2(0R11) or -SO2NR11R12; X1 is C-R10 or N; each X 2 is O or CH 2 ; each m is 1 or 2; each n is independently 0, 1 or 2; each R8 is halogen, NR11R12, N(R11)OR11, NR11NR11R12, N3, NO, N02, CHO, CH(=NR11), -CH=NHNR11, -CH=N(OR11), -CH(OR11)2, - C(=O)NR11R12, -C(=S) NR11R12, -C(-O)0R11, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl , optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C1-C8)alkyl, -S(O)n(C1-C8)alkyl, aryl(C1-C8)alkyl, CN, OR11 or SR11; each R9 or R10 is independently H, halogen, NR11R12, N(R11)OR11, N(R11)N(R11)(R12), N3, NO, NO2, CHO, CN, -CH(=NR11), -CH=NNH (R11), -CH=N(OR11), -CH(OR11)2, -C(=O)NR11R12, -C(=S)NR11R12, -C(=O)0R11, R11, OR11 or SR11; each R11 or R12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl , -C(=O)(C1C8)alkyl, -S(O)n(C1-C8)alkyl, aryl(C1-C8)alkyl or Si(R3)3; or R11 and R12 together with the nitrogen to which they are both attached form a 3- to 7-membered heterocyclic ring in which any carbon atom of said heterocyclic ring may optionally be replaced by -O-, -S(O)n- or -NRa-; or R11 and R12 together are -Si(R3)2(X2)mSi(R3)2-; each R 20 is independently H, (C 1 -C 8 )alkyl, substituted (C 1 -C 8 )alkyl or halo; wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or aryl(C1-C8)alkyl in each R1, R3, R4, R5, R6 R18 R19, R20, R11 or R12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2 or ORa; and wherein one or more non-terminal carbon atoms in each of said (C1-C8) alkyls is optionally replaced by -O-, -S(O)n- or -NRa-; said process comprising: (a) providing a compound of Formula II or an acceptable salt thereof; wherein R 16 is: OH, OR 18 , -OC(O)OR 18 or -OC(O)R 18 ; (b) treating the compound of Formula II with a cyanide reagent and Lewis acid; how the compound of Formula I is formed; with the proviso that when the compound of Formula II is: wherein X 1 is CH or N, R 1 is CH 3 , R 8 is NH 2 and R 9 is NH 2 or H or; where X1 is CH, R1 is CH3, R8 is OH and R9 is NH2 or; where X 1 is CH, each R 1 and R 9 are H and R 8 is NH 2 ; then the cyanide reagent is not (CH3)3SiCN or the mentioned Lewis acid is not BF3- O(CH2)CH3)2. 2.    Postupak prema zahtevu 1, u kome je Lewisova kiselina (R20)3CS(O)2OSi(R1)3 ili metalna so (R20)3CS(O)2OH; najmanje dva R20 su halogen; i navedeni metal je odabran iz grupe koju čine: aluminijum, galijum, indijum, talijum, kalaj, olovo, bizmut, zemno-alkalni metali, prelazni metali i lantanidi.2. The process according to claim 1, wherein the Lewis acid is (R20)3CS(O)2OSi(R1)3 or a metal salt (R20)3CS(O)2OH; at least two R20 are halogen; and said metal is selected from the group consisting of: aluminum, gallium, indium, thallium, tin, lead, bismuth, alkaline earth metals, transition metals and lanthanides. 3. Postupak prema zahtevu 1 ili 2, u kome je jedinjenje Formule I jedinjenje Formule lb: ili njegova so i jedinjenje Formule II je predstavljeno Formulom llb: ili njegovom soli.3. A process according to claim 1 or 2, wherein the compound of Formula I is a compound of Formula lb: or a salt thereof and the compound of Formula II is represented by Formula llb: or a salt thereof. 4. Postupak prema ma kom od zahteva 1-3, gde R16 je -OH ili OR18.4. Process according to any of claims 1-3, where R16 is -OH or OR18. 5. Postupak prema ma kom od zahteva 1-4, gde je jedinjenje Formule lb predstavljeno Formulom lc: ili njegova so i jedinjenje Formule llbje predstavljeno Formulom llc: ili njegovom soli.5. A process according to any one of claims 1-4, wherein the compound of Formula lb is represented by Formula lc: or a salt thereof and the compound of Formula llb is represented by Formula llc: or a salt thereof. 6.    Postupak prema ma kom od zahteva 2-5, gde je svaki R20 F, a cijanidni reagens je (CH3)3SiCN.6. A process according to any one of claims 2-5, wherein each R 20 is F and the cyanide reagent is (CH 3 ) 3 SiCN. 7.    Postupak prema ma kom od zahteva 1-6, gde je Lewisova kiselina CF3S(O)2OSi(CH3)3 ili metalna so CF3S(O)2OH pri čemu je navedeni metal indijum.7. A process according to any one of claims 1-6, wherein the Lewis acid is CF3S(O)2OSi(CH3)3 or a metal salt of CF3S(O)2OH wherein said metal is indium. 8.    Postupak prema ma kom od zahteva 1-7, gde je X2 CFI.8. The method according to any one of claims 1-7, wherein X2 is CFI. 9.    Postupak prema zahtevu 3, koji dalje obuhvata postupak za proizvodnju jedinjenja Formule llb u kom je R16 OH, postupak obuhvata: obezbeđivanje jedinjenja Formule lllb: obradu jedinjenja Formule lllb sa organometalnim jedinjenjem Formule IV: u kojoj je M MgX3 ili Li i X3 je halogen; na koji način se formira jedinjenje Formule llb u kome je R16 OH; uz uslov da kada M je Li, jedinjenje Formule llb nije jedinjenje Formule VII u kom je R17 OFI; i (a)    X1 je CH, R1 je CH3, R8 je NH2 i R9 je NH2 ili H; ili (b)    X1 je CH, R1 je CH3, R8 je OH i R9 je NH2; ili (c)    X1 je CH, svaki R1 i R9 su H i R8 je NH2; ili (d)    X1 je N, R1 je CH3, R8je NH2 i R9 je H, NH2 ili SCH3; ili (e)    X1 je N, R1 je CH3l R8 je SCH3 ili NHCH3 i R9 je SCH3; ili (f)    X1 je N, R1 je CH3, R8 je OCH3 i R9 je SCH3, SO2CH3 ili NH2.9. A process according to claim 3, further comprising a process for producing a compound of Formula llb wherein R 16 is OH, the process comprising: providing a compound of Formula llb: treating a compound of Formula llb with an organometallic compound of Formula IV: wherein M is MgX 3 or Li and X 3 is halogen; how is the compound of Formula llb in which R16 is OH formed; with the proviso that when M is Li, the compound of Formula llb is not a compound of Formula VII wherein R 17 is OFI; and (a)    X 1 is CH, R 1 is CH 3 , R 8 is NH 2 and R 9 is NH 2 or H; or (b)    X1 is CH, R1 is CH3, R8 is OH and R9 is NH2; or (c)    X 1 is CH, each R 1 and R 9 are H and R 8 is NH 2 ; or (d)    X 1 is N, R 1 is CH 3 , R 8 is NH 2 and R 9 is H, NH 2 or SCH 3 ; or (e)    X 1 is N, R 1 is CH 3 , R 8 is SCH 3 or NHCH 3 and R 9 is SCH 3 ; or (f)    X 1 is N, R 1 is CH 3 , R 8 is OCH 3 and R 9 is SCH 3 , SO 2 CH 3 or NH 2 . 10.    Postupak prema zahtevu 9, u kome je M MgX3.10. The process of claim 9, wherein M is MgX3. 11.    Postupak prema zahtevu 9 ili 10, u kome je X1 CH.11. The method according to claim 9 or 10, wherein X1 is CH. 12. Postupak prema zahtevu 9, koji dalje obuhvata postupak za proizvodnju jedinjenja Formule IV, postupak obuhvata: obezbeđivanje jedinjenja Formule V: u kome je X3 Cl, Br ili J i obradu jedinjenja Formule V sa organometalnim reagensom koji sadrži organomagnezijumsko ili organolitijumsko jedinjenje; na koji način se obrazuje jedinjenje Formule IV.12. The process of claim 9, which further comprises a process for producing a compound of Formula IV, the process comprising: providing a compound of Formula V: wherein X3 is Cl, Br or J and treating the compound of Formula V with an organometallic reagent comprising an organomagnesium or organolithium compound; how the compound of Formula IV is formed. 13. Postupak prema zahtevu 12, u kome organometalni reagens sadrži organomagnezijumsko jedinjenje.13. The method of claim 12, wherein the organometallic reagent comprises an organomagnesium compound. 14. Jedinjenje Formule II prema zahtevu 1, predstavljeno Formulom VI: ili njena prihvatljiva so; gde: R1 je H, (C1-C8)alkil, (C4-C8)karbociklilalkil, (C1-C8)supstituisan alkil, (C2-C8)alkenil, (C2-C8)supstituisan alkenil, (C2-C8)alkinil, (C2-C8)supstituisan alkinil, ili aril(C1-C8)alkil; svaki R2a ili R2bje nezavisno H, F ili OR4; svaki R3 je nezavisno (C1-C8)alkil, (C1-C8)supstituisan alkil, C6-C20 aril, C6-C20 supstituisan aril, C2-C20 heterociklil, C2-C20 supstituisan heterociklil, C7-C20 arilalkil, C7-C20 supstituisan arilalkil, (C1-C8) alkoksi, ili (C1-C8) supstituisan alkoksi; svaki R4 ili R7 je nezavisno H, opciono supstituisan alil, -C(R5)2R6, Si(R3)3, C(O)R5, C(O)OR5, -(C(R5)2)m-R15 ili ili bilo koja dva R4 ili R' zajedno su -C(R19)2-, -C(O)- ili - Si(R3)2(X2)mSi(R3)2-; svaki R15 je nezavisno -O-C(R5)2R6, -Si(R3)3, C(O)OR5, -OC(O)R5 ili svaki R5, R18 ili R1S je nezavisno H, (C1-C8) alkil, (C1-C8) supstituisan alkil, (C2-C8)alkenil, (C2-C8) supstituisan alkenil, (C2-C8) alkinil, (C2-C8) supstituisan alkinil, C8-C20 aril, C8-C2o supstituisan aril, C2-C20 heterociklil, C2-C20 supstituisan heterociklil, C7-C20 arilalkil ili C7-C20 supstituisan arilalkil; svaki R6 je nezavisno C6-C20 aril, C6-C20 supstituisan aril, ili opciono supstituisan heteroaril; svaki Ra je nezavisno H, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, aril(C1-C8)alkil, (C4-C8)karbociklilalkil, -C(=O)R11,     -C(=O)OR11,     -C(=O)NR11R12,     -C(=O)SR11, -S(O)R11, -S(O)2R11, -S(O)(OR11), -S(O)2(OR11) ili -SO2NR11R12; X1 je C-R10 ili N; svaki X2 je O ili CH2; svaki m je 1 ili 2; svaki n je nezavisno 0, 1 ili 2; svaki R8 je halogen, NR11R12, N(R11)OR11, NR11NR11R12, N3, NO, NO2, CHO, CH(=NR11), -CH=NHNR11, -CH=N(OR11), -CH(OR11)2, -C(=O)NR11R12, -C(=S) NR11R12, -C(-O)OR11, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C4-C8)karbociklilalkil, opciono supstituisan aril, opciono supstituisan heteroaril, -C(=O)(C1-C8)alkil, -S(O)n(C1-C8)alkil, aril(C1-C8)alkil, CN, OR11 ili SR11; svaki R9 ili R10 je nezavisno H, halogen, NR11R12, N(R11)OR11, N(R11)N(R11)(R12), N3, NO, NO2, CHO, CN, -CH(=NR11), -CH=NNH(R11), -CH=N(OR11), -CH(OR11)2, -C(=O)NR11R12, -C(=S)NR11R12, -C(=O)OR11, R11, OR11 ili SR11; svaki R11 ili R12 je nezavisno H, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8)karbociklil, (C4-C8)karbociklilalkil, opciono supstituisan aril, opciono supstituisan heteroaril, -C(=O)(C1-C8)alkil, -S(O)n(C1-C8)alkil, ari(C1-C8)alkil ili Si(R3)3; ili R11 i R12 zajedno sa azotom za koji su oba vezana obrazuju 3 do 7-člani heterociklični prsten u kom bilo koji atom ugljenika navedenog heterocikličnog prstena može opciono biti zamenjen sa -O-, -S(O)n- ili -NR3-; ili R11 i R12 zajedno su -Si(R3)2(X2)mSi(R3)2-; R17 je OH, OR18, -OC(O)OR18 ili -OC(O)R18; pri čemu svaki (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil ili aril(C1-C8)alkil u svakom R1, R3, R4 R5, R6, R18, R19, R11 ili R12 je, nezavisno, opciono supstituisan sa jednim ili više halo, hidroksi, CN, N3, N(Ra)2 ili ORa; i gde je jedan ili više atoma ugljenika, koji nisu krajnji u svakom od navedenih (C1-C8) alkila, opciono zamenjen sa -O-, -S(O)n-ili-N Ra-; uz uslov da kada je R17 OH ili OCH3, R1 je H ili CH3 i svaki R2a i R2b je OR4, onda svaki R7 i svaki R4 nije H; i uz uslov da jedinjenje Formule VI nije jedinjenje Formule VII gde je R17 OH i (a)    X1 je CH, R1 je CH3, R8 je NH2 i R9 je NH2 ili H; ili (b)    X1 je CH, R1 je CH3, R8 je OH i R9 je NH2; ili (c)    X1 je CH, svaki R1 i R9 su H i R8 je NH2; ili (d)    X1 je N, R1 je CH3, R8 je NH2 i R9 je H, NH2 ili SCH3; ili (e)    X1 je N, R1 je CH3, R8je SCH3 ili NHCH3 i R9je SCH3; ili (f)    X1 je N, R1 je CH3, R8 je OCH3 i R9 je SCH3, SO2CH3 ili NH2; ili gde je R17 OCH3, X1 je CH, svaki R1 i R9 je H i R8 je NH2.14. A compound of Formula II according to claim 1, represented by Formula VI: or an acceptable salt thereof; where: R1 is H, (C1-C8)alkyl, (C4-C8)carbocyclylalkyl, (C1-C8)substituted alkyl, (C2-C8)alkenyl, (C2-C8)substituted alkenyl, (C2-C8)alkynyl, (C2-C8)substituted alkynyl, or aryl(C1-C8)alkyl; each R 2a or R 2 is independently H, F or OR 4 ; each R3 is independently (C1-C8)alkyl, (C1-C8)substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heterocyclyl, C2-C20 substituted heterocyclyl, C7-C20 arylalkyl, C7-C20 substituted arylalkyl, (C 1 -C 8 ) alkoxy, or (C 1 -C 8 ) substituted alkoxy; each R4 or R7 is independently H, optionally substituted allyl, -C(R5)2R6, Si(R3)3, C(O)R5, C(O)OR5, -(C(R5)2)m-R15 or or any two R4 or R' together are -C(R19)2-, -C(O)- or -Si(R3)2(X2)mSi(R3)2-; each R15 is independently -O-C(R5)2R6, -Si(R3)3, C(O)OR5, -OC(O)R5 or each R5, R18 or R1S is independently H, (C1-C8) alkyl, (C1 -C8) substituted alkyl, (C2-C8)alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, C8-C20 aryl, C8-C2o substituted aryl, C2-C20 heterocyclyl, C2-C20 substituted heterocyclyl, C7-C20 arylalkyl or C7-C20 substituted arylalkyl; each R 6 is independently C 6 -C 20 aryl, C 6 -C 20 substituted aryl, or optionally substituted heteroaryl; each Ra is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, (C4-C8)carbocyclylalkyl, -C(=O)R11, -C(=O)OR11,     -C(=O)NR11R12,     -C(=O)SR11, -S(O)R11, -S(O)2R11, -S(O)(OR11), -S( O)2(OR11) or -SO2NR11R12; X1 is C-R10 or N; each X 2 is O or CH 2 ; each m is 1 or 2; each n is independently 0, 1 or 2; each R8 is halogen, NR11R12, N(R11)OR11, NR11NR11R12, N3, NO, NO2, CHO, CH(=NR11), -CH=NHNR11, -CH=N(OR11), -CH(OR11)2, - C(=O)NR11R12, -C(=S) NR11R12, -C(-O)OR11, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl , optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C1-C8)alkyl, -S(O)n(C1-C8)alkyl, aryl(C1-C8)alkyl, CN, OR11 or SR11; each R9 or R10 is independently H, halogen, NR11R12, N(R11)OR11, N(R11)N(R11)(R12), N3, NO, NO2, CHO, CN, -CH(=NR11), -CH= NNH(R11), -CH=N(OR11), -CH(OR11)2, -C(=O)NR11R12, -C(=S)NR11R12, -C(=O)OR11, R11, OR11 or SR11; each R11 or R12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl , -C(=O)(C1-C8)alkyl, -S(O)n(C1-C8)alkyl, aryl(C1-C8)alkyl or Si(R3)3; or R11 and R12 together with the nitrogen to which they are both attached form a 3- to 7-membered heterocyclic ring in which any carbon atom of said heterocyclic ring may optionally be replaced by -O-, -S(O)n- or -NR3-; or R11 and R12 together are -Si(R3)2(X2)mSi(R3)2-; R 17 is OH, OR 18 , -OC(O)OR 18 or -OC(O)R 18 ; wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or aryl(C1-C8)alkyl in each R1, R3, R4 R5, R6, R18, R19, R11 or R12 is , independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2 or ORa; and wherein one or more carbon atoms, which are not terminal in each of said (C1-C8)alkyl, are optionally replaced by -O-, -S(O)n-or-N Ra-; provided that when R17 is OH or OCH3, R1 is H or CH3 and each R2a and R2b is OR4, then each R7 and each R4 is not H; and with the proviso that the compound of Formula VI is not a compound of Formula VII wherein R 17 is OH and (a) X 1 is CH, R 1 is CH 3 , R 8 is NH 2 and R 9 is NH 2 or H; or (b)    X1 is CH, R1 is CH3, R8 is OH and R9 is NH2; or (c)    X 1 is CH, each R 1 and R 9 are H and R 8 is NH 2 ; or (d)    X 1 is N, R 1 is CH 3 , R 8 is NH 2 and R 9 is H, NH 2 or SCH 3 ; or (e) X1 is N, R1 is CH3, R8 is SCH3 or NHCH3 and R9 is SCH3; or (f)    X1 is N, R1 is CH3, R8 is OCH3 and R9 is SCH3, SO2CH3 or NH2; or wherein R 17 is OCH 3 , X 1 is CH, each R 1 and R 9 is H and R 8 is NH 2 . 15. Jedinjenje prema zahtevu 14, pri čemu je jedinjenje Formule VI predstavljeno Formulom Vlb: ili njegova prihvatljiva so.15. The compound of claim 14, wherein the compound of Formula VI is represented by Formula Vlb: or an acceptable salt thereof. 16.    Jedinjenje prema zahtevu 14 ili 15, pri čemu je R17 OH ili OR3.16. A compound according to claim 14 or 15, wherein R17 is OH or OR3. 17.    Jedinjenje prema ma kom od zahteva 14-16, pri čemu je jedinjenje Formule VI predstavljeno Formulom Vic: ili njegova prihvatljiva so, gde: R2b je OR4 ili F; svaki R4 je nezavisno -CH2R6 ili C(O)R5 gde je R5 fenil ili supstituisani fenil; R7 je Si(R3)3, C(O)R5 ili -C(R5)2R6 gde je svaki R5 nezavisno H, fenil ili supstituisani fenil; R6 je fenil ili supstituisani fenil; i ostale promenljive su kao što su definisane za Formulu VI.17. A compound according to any one of claims 14-16, wherein the compound of Formula VI is represented by Formula Vic: or an acceptable salt thereof, wherein: R2b is OR4 or F; each R 4 is independently -CH 2 R 6 or C(O)R 5 where R 5 is phenyl or substituted phenyl; R 7 is Si(R 3 ) 3 , C(O) R 5 or -C(R 5 ) 2 R 6 where each R 5 is independently H, phenyl or substituted phenyl; R 6 is phenyl or substituted phenyl; and other variables are as defined for Formula VI. 18. Jedinjenje prema ma kom od zahteva 14-17, pri čemu je X1 CH.18. A compound according to any one of claims 14-17, wherein X1 is CH. 19.    Jedinjenje prema ma kom od zahteva 14-18, pri čemu je R8 NH2 i R9 je H.19. A compound according to any one of claims 14-18, wherein R8 is NH2 and R9 is H. 20.    Jedinjenje prema zahtevu 15, koje je ili njegova prihvatljiva so.20. A compound according to claim 15, which is or an acceptable salt thereof.
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